Diuretics are the most widely prescribed class of drugs. As renal function deteriorates in patients with chronic kidney disease (CKD) whose glomerular filtration rate falls below 60 ml/min (stages 3 to 5) they become more salt-sensitive and require a low BP goal to slow the progression of their disease and to prevent the associated cardiovascular disease (CV) complications. This mandates a predictably effective diuretic. However, at CKD > 3-5, thiazides lose their efficacy. Patients are often switched to furosemide although this suffers from a number of limitations. Furosemide has a highly variable bioavailability (10 to 80%) that leads to unpredictable efficacy and its accumulation in advanced CKD leads to ototoxicity. It has a very short duration of action of about 4 hours that permit post- diuretic renal Na+ and fluid retention that limits the loss of body salt and water (efficacy) and t an abrupt action (Niagara effect) that reduces the quality of life and causes neurohumoral activation, including aldosterone secretion, that are associated with bad clinical outcomes. Torsemide is a fully effective loop diuretic that is eliminated largely by hepatic metabolism and so does not accumulate in CKD. It has a high and constant bioavailability (80- 100%) in CKD, and blocks the secretion and action of aldosterone, thereby generally maintaining serum potassium concentrations. However, it too suffers from a limited duration of action (4 -8 hours). To address this unmet need and to provide a better diuretic for hypertensive CKD, we have formulated an extended release (ER) form of torsemide that releases the drugs over 8-10 hours in solution. This grant is a proposal for a phase 1 within - subject, cross over, single dose trialto contrast torsemide ER with torsemide immediate release (IR) in 8 normal individuals on fixed Na+ and K+ intakes. Aims 1 will compare pharmakokinetics; aim 2 pharmakodynamics (Na+ and K+ balances) and aim 3 neurohurmonal activation. If successful, this will lead to a similar phase 2 trial in patients with CKD 3-5. This would be followed by an efficacy and safety trial in patients with CKD 3-5 that includes the effects of torsemide ER compared with the standard-of-care drug, furosemide, comparing antihypertensive efficacy and safety in this population.